Benchmark Concentration Research Articles

Development of a chronic inhalation reference value for hexamethylenediamine using an exposure model based on the dihydrochloride salt

The Texas Commission on Environmental Quality has developed a chronic inhalation Reference Value (ReV) for hexamethylenediamine (HMDA, CAS 124-09-4) based on respiratory effects identified in an animal study. HMDA is used in the fiber and plastics industry as an intermediate in the production of nylon, high-strength resins and polyamide adhesives. As a toxicant, HMDA acts primarily as a respiratory irritant with effects occurring in the upper respiratory tract, although systemic effects have been noted at higher concentrations. ReVs are chemical-specific air concentrations derived to protect human health. Acute and chronic ReVs were developed for HDMA based on an inhalation study conducted by the National Toxicology Program (NTP), which used the salt of HMDA, hexamethylenediamine dihydrochloride (HDDC, CAS 6055-52-3). For the chronic evaluation, rats and mice were exposed to 0, 1.6, 5, 16, 50 and 160 mg HDDC/m3 for 13 weeks. The critical effect identified for the most sensitive species was hyaline degeneration in the olfactory epithelium in mice. The data provided in this study were suitable to benchmark concentration (BMC) modeling. Dosimetric adjustments using the rat and mouse Multiple-Path Particle Dosimetry Model (version 3.0) were made to the 95% lower limit of the BMC(10) to determine the human equivalent point of departure. Uncertainty factors were applied to account for variation in sensitivity within the human population, toxicodynamic differences between mice and humans, and use of a subchronic study. The ReV was initially calculated for HDDC and then adjusted for HMDA. The chronic ReV is 1.8 µg/m3 for respirable HMDA ≤ 10 µm in diameter.

Environmental exposure to organochlorine pesticides and deficits in cochlear status in children.

The aim of this study was to examine the hypothesis that organochlorine pesticides (OCPs), hexachlorobenzene (HCB), β-hexachlorocyclohexane (β-HCH), and 1,1,1-trichloro-2,2-bis(4-chlorophenyl)ethane (p,p'-DDT) and its metabolite 1,1-dichloro-2,2-bis(4-chlorophenyl)ethylene (p,p'- DDE) are ototoxic to humans. A multivariate general linear model was designed, in which the statistical relation between blood serum concentrations of HCB, β-HCH, p,p'-DDT, or p,p'-DDE at different ages (at birth, 6, 16, and 45 months) and the distortion product otoacoustic emissions (DPOAEs) was treated as multivariate outcome variables. Polychlorinated biphenyl (PCB) congeners and OCPs were strongly correlated in serum of children from our cohort. To ascertain that the association between DPOAEs at a given frequency and concentration of a pesticide is not influenced by PCBs or other OCP also present in serum, we calculated benchmark concentrations (BMCs) relating DPOAEs to a serum pesticide alone and in presence of confounding PCB-153 or other OCPs. We found that BMCs relating DPOAEs to serum pesticides are not affected by confounders. DPOAE amplitudes were associated with serum OCPs at all investigated time intervals, however, in a positive way with prenatal exposure and in a negative way with all postnatal exposures. We observed tonotopicity in the association of pesticides with amplitude of DPOAEs as its strength was frequency dependent. We conclude that exposure to OCPs in infancy at environmental concentrations may be associated with hearing deficits.

Sugar reduction of skim chocolate milk and viability of alternative sweetening through lactose hydrolysis

Milk consumption by Americans has not met the standards of the Dietary Guidelines for Americans. Chocolate milk can improve milk consumption, especially by children, due to its color and taste. However, the high sugar content of chocolate milk is a cause for concern about its healthfulness, resulting in its removal from some school lunch programs. It is important to reduce the sugar content of chocolate milk and still maintain acceptability among consumers. It is also important to investigate other natural alternatives to sweetening. The objectives of this study were to identify the different sweetness intensity perceptions of sucrose in water and various dairy matrices, to identify the acceptable reduction in sweet taste for chocolate milk for both young adults (19–35yr) and children (5–13yr), and to determine if lactose hydrolysis is a viable alternative. Threshold and power function studies were used to determine the benchmark concentration of sucrose in chocolate milk. The acceptability of sugar reduction from the benchmark concentration for both young adults and children and the acceptability of lactose hydrolyzed chocolate milk (4°C for 24h) with added lactose for young adults were evaluated. Acceptability results demonstrated that sugar reduction in chocolate milk is possible for both young adults and children as long as it does not exceed a 30% reduction (from 205mM). Lactose hydrolysis of added lactose was used to achieve the sweetness of sucrose in chocolate milk but required >7.5% (wt/vol) added lactose, which contributed undesirable calories, indicating that lactose hydrolysis may be more suitable for other dairy beverages that require less added sugar. The findings of this study demonstrate consumer acceptance of reduced-sugar chocolate milk and a possible way to use lactose hydrolysis in dairy beverages.

Use of the ES-D3 cell differentiation assay, combined with the BeWo transport model, to predict relative in vivo developmental toxicity of antifungal compounds

We investigated the applicability of the ES-D3 cell differentiation assay combined with the in vitro BeWo transport model to predict the relative in vivo developmental toxicity potencies. To this purpose, the in vitro developmental toxicity of five antifungal compounds was investigated by characterizing their inhibitory effect on the differentiation of ES-D3 cells into cardiomyocytes. The BeWo transport model, consisting of BeWo b30 cells grown on transwell inserts and mimicking the placental barrier, was used to determine the relative placental transport velocity. The ES-D3 cell differentiation data were first compared to benchmark doses (BMDs) for in vivo developmental toxicity as derived from data reported in the literature. Correlation between the benchmark concentration for 50% effect (BMCd50) values, obtained in the ES-D3 cell differentiation assay, with in vivo BMD10 values showed a reasonable correlation (R2=0.57). When the ES-D3 cell differentiation data were combined with the relative transport rates obtained from the BeWo model, the correlation with the in vivo data increased (R2=0.95). In conclusion, we show that the ES-D3 cell differentiation assay is able to better predict the in vivo developmental toxicity ranking of antifungal compounds when combined with the BeWo transport model, than as a stand-alone assay.

Risk assessment for children exposed to DDT residues in various milk types from the Greek market

The occurrence of residues of DDT and its metabolites was monitored in 196 cow milk samples of various pasteurized commercial types collected from the Greek market. Residue levels were determined by GC-MS analysis. In 97.4% of the samples at least one DDT isomer or one of the DDT metabolites was detected, in levels not exceeding the maximum permitted residue level by the EU. Hazard Index for both carcinogenic and non-carcinogenic effects was estimated under two assumptions: a) using DDT concentrations from positive samples and b) imputing LOD/2 as an arbitrary concentration for negative samples. No statistically significant differences in detected or summed residue (p > 0.05) concentrations between different milk types were observed, with the exception of specific metabolites of DDT in some milk types. Exposure assessment scenarios were developed for children aged 1, 3, 5, 7 and 12 years old based on estimated body weights and daily milk consumption. Hazard Indices for non-carcinogenic effects were below 0.109 covering also carcinogenic effects according to WHO approach. The cancer risk values for carcinogenic effects according to the US EPA Cancer Benchmark Concentration approach, ranged from 0.4 to 18. For both effects the highest values were calculated for the 1- to 3-year-old age groups.

Diversity Outbred Mice Identify Population-Based Exposure Thresholds and Genetic Factors that Influence Benzene-Induced Genotoxicity.

BackgroundInhalation of benzene at levels below the current exposure limit values leads to hematotoxicity in occupationally exposed workers.ObjectiveWe sought to evaluate Diversity Outbred (DO) mice as a tool for exposure threshold assessment and to identify genetic factors that influence benzene-induced genotoxicity.MethodsWe exposed male DO mice to benzene (0, 1, 10, or 100 ppm; 75 mice/exposure group) via inhalation for 28 days (6 hr/day for 5 days/week). The study was repeated using two independent cohorts of 300 animals each. We measured micronuclei frequency in reticulocytes from peripheral blood and bone marrow and applied benchmark concentration modeling to estimate exposure thresholds. We genotyped the mice and performed linkage analysis.ResultsWe observed a dose-dependent increase in benzene-induced chromosomal damage and estimated a benchmark concentration limit of 0.205 ppm benzene using DO mice. This estimate is an order of magnitude below the value estimated using B6C3F1 mice. We identified a locus on Chr 10 (31.87 Mb) that contained a pair of overexpressed sulfotransferases that were inversely correlated with genotoxicity.ConclusionsThe genetically diverse DO mice provided a reproducible response to benzene exposure. The DO mice display interindividual variation in toxicity response and, as such, may more accurately reflect the range of response that is observed in human populations. Studies using DO mice can localize genetic associations with high precision. The identification of sulfotransferases as candidate genes suggests that DO mice may provide additional insight into benzene-induced genotoxicity.CitationFrench JE, Gatti DM, Morgan DL, Kissling GE, Shockley KR, Knudsen GA, Shepard KG, Price HC, King D, Witt KL, Pedersen LC, Munger SC, Svenson KL, Churchill GA. 2015. Diversity Outbred mice identify population-based exposure thresholds and genetic factors that influence benzene-induced genotoxicity. Environ Health Perspect 123:237–245; http://dx.doi.org/10.1289/ehp.1408202

Characterization of fish hold effluent discharged from commercial fishing vessels into harbor waters

Fish hold effluent and the effluent produced from the cleaning of fish holds may contain organic material resulting from the degradation of seafood and cleaning products (e.g., soaps and detergents). This effluent is often discharged by vessels into near shore waters and, therefore, could have the potential to contribute to water pollution in bays and estuaries. We characterized effluent from commercial fishing vessels with holds containing refrigerated seawater, ice slurry, or chipped ice. Concentrations of trace heavy metals, wet chemistry parameters, and nutrients in effluent were compared to screening benchmarks to determine if there is a reasonable potential for effluent discharge to contribute to nonattainment of water quality standards. Most analytes (67%) exceeded their benchmark concentration and, therefore, may have the potential to pose risk to human health or the environment if discharges are in significant quantities or there are many vessels discharging in the same areas.

Ciprofloxacin conjugated zinc oxide nanoparticle: A camouflage towards multidrug resistant bacteria

Gradual development of antibiotic resistant bacteria is producing severe global threat. Newer strategies are now being employed in order to control the microbial infections and to reduce the mortality as well as infection rates. Herein we describe successful synthesis of ZnO nanoparticles (ZNP) under microwave assisted condition followed by functionalization with ciprofloxacin, an antibiotic, using EDC/NHS chemistry. Successful conjugation of ciprofloxacin was confirmed by FTIR spectra. Ciprofloxacin-conjugated ZnO nanoparticles (ZN-CIP) exhibited excellent antibacterial activity against clinically isolated multidrug resistant bacterial strains of Escherichia coli, Staphylococcus aureus and Klebsiella sp. ZNP were small in size with particle size distribution 18–20 nm as obtained from transmission electron microscope (TEM). Surface topology was obtained from atomic force microscopic (AFM) image and x-ray diffraction confirmed that ZNP possessed hexagonal crystal structure. A concentration of 10 µg/mL of ZN-CIP was a benchmark concentration. During evaluation of minimum inhibitory concentration (MIC) values, similar concentration of antibiotic was incapable of producing antibacterial activity.

Comparative chemical sensitivity between marine Australian and Northern Hemisphere ecosystems: Is an uncertainty factor warranted for water‐quality–guideline setting?

The lack of Australian species data has pragmatically led to the use of toxicological data from the Northern Hemisphere to develop water-quality guidelines. However, it is unknown whether Australian species and ecosystems are equally as sensitive and if an uncertainty factor is warranted for Australian guideline setting. In the present study, it is hypothesized that an uncertainty factor is not required. This was tested by generating species sensitivity distributions by 2 parametric methods using marine Northern Hemisphere and Australian/New Zealand data. Sufficient acute data were found for only 3 compounds: 4-chlorophenol, phenol, and ammonia. For ammonia and 4-chlorophenol, the 95% species protection levels generated with Australian and Northern Hemisphere data were essentially the same. For phenol, protection levels derived from Australian data were approximately 10-fold higher. Therefore, the derived benchmark concentration from Northern Hemisphere data should be protective. It is tentatively concluded that there is no need for an uncertainty factor when deriving water-quality guidelines for marine Australian ecosystems using Northern Hemisphere data. It is, however, noted that this is based on only 3 compounds.

Dioxin relative effect potencies calculated from human thyroid data

We have recently published a paper1 on derivation of relative effect potencies (REPs) of a group of potent endocrine-active chemicals, the dioxin-like compounds (DLCs). The toxic equivalency factors (TEFs), assigned on the basis of the REPs, are an important component in the risk assessment of DLCs human exposures. At present, this concept is based mainly on in vivo animal experiments using oral dosage. Consequently, the current human TEFs derived from mammalian experiments are applicable only for exposure situations in which oral ingestion occurs. Nevertheless, these “intake” TEFs are commonly—but incorrectly—used by regulatory authorities to calculate “systemic” toxic equivalents (TEQs) based on human blood and tissue concentrations, which are used as biomarkers for either exposure or effect.We sought to determine REPs for systemic human concentrations of dioxin-like mixture components using thyroid volume or serum-free thyroxine (FT4) concentration as the outcomes of interest. We used a benchmark concentration and a regression-based approach to compare the strength of association between each DLC and the thyroid end points in 320 adults residing in an organochlorine-polluted area of eastern Slovakia. We found that REPs calculated from thyroid volume and FT4 were similar. The regression coefficient (β)-derived REP data from thyroid volume and FT4 level were correlated with the World Health Organization (WHO) TEF values (Spearman r = 0.69, P = 0.01 and r = 0.62, P = 0.03, respectively). The calculated REPs were mostly within the minimum and maximum values for in vivo REPs derived by other investigators (Haws et al. 2006). We concluded that our REPs calculated from thyroid end points realistically reflect human exposure scenarios because they are based on chronic, low-dose human exposures and on biomarkers reflecting body burden. Compared with previous results, our REPs suggest higher sensitivity to the effects of DLCs.

Assessment of beating parameters in human induced pluripotent stem cells enables quantitative in vitro screening for cardiotoxicity

Human induced pluripotent stem cell (iPSC)-derived cardiomyocytes show promise for screening during early drug development. Here, we tested a hypothesis that in vitro assessment of multiple cardiomyocyte physiological parameters enables predictive and mechanistically-interpretable evaluation of cardiotoxicity in a high-throughput format. Human iPSC-derived cardiomyocytes were exposed for 30min or 24h to 131 drugs, positive (107) and negative (24) for in vivo cardiotoxicity, in up to 6 concentrations (3nM to 30uM) in 384-well plates. Fast kinetic imaging was used to monitor changes in cardiomyocyte function using intracellular Ca2+ flux readouts synchronous with beating, and cell viability. A number of physiological parameters of cardiomyocyte beating, such as beat rate, peak shape (amplitude, width, raise, decay, etc.) and regularity were collected using automated data analysis. Concentration–response profiles were evaluated using logistic modeling to derive a benchmark concentration (BMC) point-of-departure value, based on one standard deviation departure from the estimated baseline in vehicle (0.3% dimethyl sulfoxide)-treated cells. BMC values were used for cardiotoxicity classification and ranking of compounds. Beat rate and several peak shape parameters were found to be good predictors, while cell viability had poor classification accuracy. In addition, we applied the Toxicological Prioritization Index (ToxPi) approach to integrate and display data across many collected parameters, to derive “cardiosafety” ranking of tested compounds. Multi-parameter screening of beating profiles allows for cardiotoxicity risk assessment and identification of specific patterns defining mechanism-specific effects. These data and analysis methods may be used widely for compound screening and early safety evaluation in drug development.

Comparison of multianalyte proficiency test results by sum of ranking differences, principal component analysis, and hierarchical cluster analysis

Sum of ranking differences (SRD) was applied for comparing multianalyte results obtained by several analytical methods used in one or in different laboratories, i.e., for ranking the overall performances of the methods (or laboratories) in simultaneous determination of the same set of analytes. The data sets for testing of the SRD applicability contained the results reported during one of the proficiency tests (PTs) organized by EU Reference Laboratory for Polycyclic Aromatic Hydrocarbons (EU-RL-PAH). In this way, the SRD was also tested as a discriminant method alternative to existing average performance scores used to compare mutlianalyte PT results. SRD should be used along with the z scores--the most commonly used PT performance statistics. SRD was further developed to handle the same rankings (ties) among laboratories. Two benchmark concentration series were selected as reference: (a) the assigned PAH concentrations (determined precisely beforehand by the EU-RL-PAH) and (b) the averages of all individual PAH concentrations determined by each laboratory. Ranking relative to the assigned values and also to the average (or median) values pointed to the laboratories with the most extreme results, as well as revealed groups of laboratories with similar overall performances. SRD reveals differences between methods or laboratories even if classical test(s) cannot. The ranking was validated using comparison of ranks by random numbers (a randomization test) and using seven folds cross-validation, which highlighted the similarities among the (methods used in) laboratories. Principal component analysis and hierarchical cluster analysis justified the findings based on SRD ranking/grouping. If the PAH-concentrations are row-scaled, (i.e., z scores are analyzed as input for ranking) SRD can still be used for checking the normality of errors. Moreover, cross-validation of SRD on z scores groups the laboratories similarly. The SRD technique is general in nature, i.e., it can be applied to any experimental problem in which multianalyte results obtained either by several analytical procedures, analysts, instruments, or laboratories need to be compared.

Comparative hazard identification of nano- and micro-sized cerium oxide particles based on 28-day inhalation studies in rats

There are many uncertainties regarding the hazard of nanosized particles compared to the bulk material of the parent chemical. Here, the authors assess the comparative hazard of two nanoscale (NM-211 and NM-212) and one microscale (NM-213) cerium oxide materials in 28-day inhalation toxicity studies in rats (according to Organisation for Economic Co-operation and Development technical guidelines). All three materials gave rise to a dose-dependent pulmonary inflammation and lung cell damage but without gross pathological changes immediately after exposure. Following NM-211 and NM-212 exposure, epithelial cell injury was observed in the recovery groups. There was no evidence of systemic inflammation or other haematological changes following exposure of any of the three particle types. The comparative hazard was quantified by application of the benchmark concentration approach. The relative toxicity was explored in terms of three exposure metrics. When exposure levels were expressed as mass concentration, nanosized NM-211 was the most potent material, whereas when expression levels were based on surface area concentration, micro-sized NM-213 material induced the greatest extent of pulmonary inflammation/damage. Particles were equipotent based on particle number concentrations. In conclusion, similar pulmonary toxicity profiles including inflammation are observed for all three materials with little quantitative differences. Systemic effects were virtually absent. There is little evidence for a dominant predicting exposure metric for the observed effects.

Relative Effect Potency Estimates of Dioxin-like Activity for Dioxins, Furans, and Dioxin-like PCBs in Adults Based on Two Thyroid Outcomes

Background: Toxic equivalency factors (TEFs) are an important component in the risk assessment of dioxin-like human exposures. At present, this concept is based mainly on in vivo animal experiments using oral dosage. Consequently, the current human TEFs derived from mammalian experiments are applicable only for exposure situations in which oral ingestion occurs. Nevertheless, these “intake” TEFs are commonly—but incorrectly—used by regulatory authorities to calculate “systemic” toxic equivalents (TEQs) based on human blood and tissue concentrations, which are used as biomarkers for either exposure or effect.Objectives: We sought to determine relative effect potencies (REPs) for systemic human concentrations of dioxin-like mixture components using thyroid volume or serum free thyroxine (FT4) concentration as the outcomes of interest.Methods: We used a benchmark concentration and a regression-based approach to compare the strength of association between each dioxin-like compound and the thyroid end points in 320 adults residing in an organochlorine-polluted area of eastern Slovakia.Results: REPs calculated from thyroid volume and FT4 were similar. The regression coefficient (β)-derived REP data from thyroid volume and FT4 level were correlated with the World Health Organization (WHO) TEF values (Spearman r = 0.69, p = 0.01 and r = 0.62, p = 0.03, respectively). The calculated REPs were mostly within the minimum and maximum values for in vivo REPs derived by other investigators.Conclusions: Our REPs calculated from thyroid end points realistically reflect human exposure scenarios because they are based on chronic, low-dose human exposures and on biomarkers reflecting body burden. Compared with previous results, our REPs suggest higher sensitivity to the effects of dioxin-like compounds.

Estimating population‐level HC5 for copper using a species sensitivity distribution approach

Estimation of population-level benchmark concentrations for protecting aquatic organisms from chemicals is important for value-relevant ecological risk assessments. By employing a species sensitivity distribution (SSD) approach, the authors aimed to derive the population-level hazardous concentration for 5% of species (PHC5) for copper. Based on available information on copper toxicity and population models, the authors estimated population threshold concentrations at which the population size is stable (that is, 0 net population growth) for 13 freshwater species (3 algal, 6 invertebrate, and 4 fish species). The PHC5 for copper was then estimated (6.8 µg/L; 95% confidence interval [CI], 1.8-13.6 µg/L), by fitting a log-normal distribution to the population threshold concentrations obtained. The close overlap between the present study's estimate of the PHC5 and a field-derived threshold concentration suggests that the population-level SSD approach provides a reasonable level of protection for species richness in the natural environment. By contrast, and counterintuitively, the authors' estimate was comparable with the individual-level HC5 reported in the European Union risk assessment. Although the present study cannot determine the underlying reasons for the similar figures, the result provides an indication that the margin between individual-level and population-level benchmarks derived from SSD approaches can be very small. The results therefore suggest that attention is needed to achieve population-level protection using an individual-level SSD approach.

Study of the dispersion/settling of oil-mineral-aggregates using particle tracking model and assessment of their potential risks

A random walk particle tracking model was used to simulate the motions of oil-mineral-aggregates (OMAs) under hydrodynamic conditions involving wave-induced velocities, random velocities due to turbulence, and the settling velocity due to gravity. Wave-induced and settling velocities for OMAs determined from the application of Stokes’s theory and empirical equations derived from experimental data were used in a series of simulations to evaluate the effects of wave characteristics, particle size distribution, and settling/floating velocity on the transport of OMAs formed from two different types of minerals. The study found that the wave effect on advection/diffusion is of secondary importance when compared to tidal currents and turbulence induced velocity. To assess the risk of OMAs to benthic organisms, predicted environmental concentrations (PEC) was compared to the benchmark concentration (BC) derived for eight different hydrocarbon groups. The simulation results indicate that no risk from both aliphatic and aromatic hydrocarbons can be found for the two cases described in this paper with a 1,000 tonnes spill. The study also showed that aromatic hydrocarbons posed more risk than aliphatic hydrocarbons. For both aliphatic and aromatic hydrocarbons, the C9–C12 group posed greater risk than other groups.

Exposure Assessment Framework for Antimicrobial Copper Use in Urbanized Areas

Copper is used as an antimicrobial agent in building materials such as algae-resistant roofing shingles and treated wood products for decks, fences, and utility poles used in urbanized areas. Releases from these materials may pose risks to aquatic and terrestrial organisms. Copper exposures in surface water, sediment, and soil were estimated for a hypothetical urban setting using the TREX watershed model. Drainage and soil characteristics were based on an existing watershed. Urban landscape characteristics were developed from data regarding housing densities and copper use in building materials. This setting provides a spatially distributed, upper-bound assessment scenario. Release rates from algae-resistant shingles and treated wood were defined based on surface area and rainfall. Simulations for the urban landscapes were performed for a 10-year period. Simulation results were used to evaluate exceedences of benchmark concentrations for water, sediment, and soil. For algae-resistant shingles, exposures did not exceed benchmarks in any media. For treated wood, exposures did not exceed sediment and soil benchmarks, and surface water benchmarks were exceeded on 2 days in 10 years. Based on this analysis, copper use as an antimicrobial agent in algae resistant shingles and treated wood is not expected to pose significant adverse environmental risks on an individual use basis.

Risk Assessments of Exposure to Airborne Volatile Organic Compounds in Gumi Industrial Complex Area, Korea

This paper carried out the lifetime risk assessment of exposure to airborne Volatile Organic Compounds (VOCs) in environmental atmosphere in one Korean industrial city-Gumi based on the measured concentrations of VOCs at five representative outdoor monitoring sites. According to the measured VOCs concentration, toluene, trichloroethylene and dichloromethane are three main VOCs in Gumi. The carcinogenic risks for each of the carcinogenic VOCs in all five designated sites are more than the benchmark concentration (1.0E-6). The predominant risks in industrial areas are chloroform, benzene and trichloroethylene. And the predominant risks in other sites are benzene and chloroform and their proportions to cancer risk are not less than 90%. Based the analysis, effectively decreasing the emission of chloroform, benzene, Trichloroethylene and 1,2-dichloropropane will rapidly reduce the cancer risks in Gumi.

Localized pleural thickening: Smoking and exposure to Libby vermiculite

There is limited research on the combined effects of smoking and asbestos exposure on risk of localized pleural thickening (LPT). This analysis uses data from the Marysville cohort of workers occupationally exposed to Libby amphibole asbestos (LAA). Workers were interviewed to obtain work and health history, including ever/never smoking and chest X-rays. Cumulative exposure estimates were developed on the basis of fiber measurements from the plant and work history. Benchmark concentration (BMC) methodology was used to evaluate the exposure-response relationship for exposure to LAA and a 10% increased risk of LPT, considering potential confounders and statistical model forms. There were 12 LPT cases among 118 workers in the selected study population. The mean exposure was 0.42 (SD=0.77) fibers/cc-year, and the prevalence of smoking history was 75.0% among cases and 51.9% among non-cases. When controlling for LAA exposure, smoking history was of borderline statistical significance (P-value=0.099), and its inclusion improved model fit, as measured by Akaike's Information Criterion. A comparison of BMC estimates was made to gauge the potential effect of smoking status. The BMC was 0.36 fibers/cc-year, overall. The BMC for non-smokers was approximately three times as high (1.02 fibers/cc-year) as that for the full cohort, whereas the BMC for smokers was about 1/2 that of the full cohort (0.17 fibers/cc-year).

Guide values for indoor air: update of the German risk assessment procedure (basic scheme)

In order to harmonize recommendations on the evaluation of indoor air contamination by means of guide values, the Ad-hoc Working Group of the Indoor Air Hygiene Commission of the German Federal Environment Agency and of the Supreme State Health Authorities (IRK / AOLG Ad-hoc working group) has updated the procedures for toxicologically derived indoor air guide values for individual substances or groups of substances. In general two guide values are proposed by the committee. Guide value II (RW II) is an adverse effect-related value, based on current toxicological and epidemiological knowledge of a substance's effect threshold, usually the LOAEC or a benchmark concentration from human or animal studies. Guide value I (RW I) represents the concentration of a substance in indoor air for which, when considered individually, there is no evidence at present that even lifelong exposure is expected to have any adverse health impacts. Individual steps in the derivation of guide value II are: i) identification of the critical study and the Point of Departure (POD), conversion from short term to continuous exposure by adjustment for ii) study length (subacute - subchronic - chronic) and iii) exposure duration (hours/day and days/week), extrapolation from animal to man by iv) interspezies variability (allometric, toxicokinetic and dynamic factors), consideration of sensitive individuals by v) intraspecies variability (kinetic and dynamic factor), and vi) physiologic differences within the population( i.e. children factor), and finally vii) consideration of the quality of database. The quality of the pivotal study is assessed according to the criteria proposed by Klimisch et al. (1997). The assessment factors have been harmonized with recent recommendations by WHO (IAQG 2010) and ECHA guidance document R 8. RW I is derived from RW II by introduction of an additional factor (usually 10) but can also be derived if no reliable LOAEC is available from a "No observed adverse effect concentration" (NOAEC).A template containing the key information on the chemical and the critical study and transparently presenting the assessment factors and derivation of the guide values and a glossary of terms complete the recommendation.